γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer

Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of gamma-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the gamma and delta isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the gamma and delta forms of tocopherol. Knockout of PPAR-gamma and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-gamma-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-gamma-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGF beta 2 are down-regulated after treatment with GT3, with concomitant disruptions in TGF beta receptor I, SMAD-2, p38, and NF-kappa B signaling. (C) 2011 Elsevier Inc. All rights reserved.